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Title: Computational analysis reveals the coupling between bistability and the sign of a feedback loop in a TGF-?1 activation model
Authors: Li, H 
Venkatraman, L 
Narmada, B.C
White, J.K
Yu, H 
Tucker-Kellogg, L. 
Keywords: calcium
transforming growth factor beta1
biological model
physiological feedback
signal transduction
Feedback, Physiological
Models, Biological
Signal Transduction
Transforming Growth Factor beta1
Issue Date: 2017
Citation: Li, H, Venkatraman, L, Narmada, B.C, White, J.K, Yu, H, Tucker-Kellogg, L. (2017). Computational analysis reveals the coupling between bistability and the sign of a feedback loop in a TGF-?1 activation model. BMC Systems Biology 11 : 136. ScholarBank@NUS Repository.
Abstract: Background: Bistable behaviors are prevalent in cell signaling and can be modeled by ordinary differential equations (ODEs) with kinetic parameters. A bistable switch has recently been found to regulate the activation of transforming growth factor-?1 (TGF-?1) in the context of liver fibrosis, and an ordinary differential equation (ODE) model was published showing that the net activation of TGF-?1 depends on the balance between two antagonistic sub-pathways. Results: Through modeling the effects of perturbations that affect both sub-pathways, we revealed that bistability is coupled with the signs of feedback loops in the model. We extended the model to include calcium and Krüppel-like factor 2 (KLF2), both regulators of Thrombospondin-1 (TSP1) and Plasmin (PLS). Increased levels of extracellular calcium, which alters the TSP1-PLS balance, would cause high levels of TGF-?1, resembling a fibrotic state. KLF2, which suppresses production of TSP1 and plasminogen activator inhibitor-1 (PAI1), would eradicate bistability and preclude the fibrotic steady-state. Finally, the loop PLS - TGF-?1 - PAI1 had previously been reported as negative feedback, but the model suggested a stronger indirect effect of PLS down-regulating PAI1 to produce positive (double-negative) feedback in a fibrotic state. Further simulations showed that activation of KLF2 was able to restore negative feedback in the PLS - TGF-?1 - PAI1 loop. Conclusions: Using the TGF-?1 activation model as a case study, we showed that external factors such as calcium or KLF2 can induce or eradicate bistability, accompanied by a switch in the sign of a feedback loop (PLS - TGF-?1 - PAI1) in the model. The coupling between bistability and positive/negative feedback suggests an alternative way of characterizing a dynamical system and its biological implications. © 2017 The Author(s).
Source Title: BMC Systems Biology
ISSN: 17520509
DOI: 10.1186/s12918-017-0508-z
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